scholarly journals Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

2021 ◽  
Vol 13 ◽  
Author(s):  
Cellas A. Hayes ◽  
Brandon G. Ashmore ◽  
Akshaya Vijayasankar ◽  
Jessica P. Marshall ◽  
Nicole M. Ashpole
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Growth Factor ◽  
Critical Role ◽  
Advanced Age ◽  
Glutamate Excitotoxicity ◽  
Insulin Like Growth Factor ◽  
Age Related ◽  
Increased Risk ◽  
And Function

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

scholarly journals IGF-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

2021 ◽  
Author(s):  
Cellas A Hayes ◽  
Brandon G Ashmore ◽  
Akshaya Vijayasankar ◽  
Jessica P Marshall ◽  
Nicole M Ashpole
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Critical Role ◽  
Advanced Age ◽  
Glutamate Excitotoxicity ◽  
Microvascular Endothelial Cell ◽  
Neural Function ◽  
Age Related ◽  
Increased Risk ◽  
And Function

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF- 1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

Characterization, regulation, and function of specific cell membrane receptors for insulin-like growth factor I on bone endothelial cells

2009 ◽  
Vol 9 (3) ◽  
pp. 329-337 ◽  
Author(s):  
Gianna Fiorelli ◽  
Claudio Orlando ◽  
Susanna Benvenuti ◽  
Francesco Franceschelli ◽  
Sandro Bianchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Cell Membrane ◽  
Membrane Receptors ◽  
Specific Cell ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Growth Factor I ◽  
And Function

scholarly journals Insulin-Like Growth Factor-II and Ischemic Stroke—A Prospective Observational Study

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 499
Author(s):  
Daniel Åberg ◽  
N. David Åberg ◽  
Katarina Jood ◽  
Petra Redfors ◽  
Christian Blomstrand ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Functional Outcome ◽  
Serum Levels ◽  
Adult Brain ◽  
Insulin Like Growth Factor ◽  
Increased Risk ◽  
Factor Ii ◽  
Study Population

Insulin-like growth factor-II (IGF-II) regulates prenatal brain development, but the role in adult brain function and injury is unclear. Here, we determined whether serum levels of IGF-II (s-IGF-II) are associated with mortality and functional outcome after ischemic stroke (IS). The study population comprised ischemic stroke cases (n = 492) and controls (n = 514) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months and 2 years using the modified Rankin Scale (mRS), and additionally, survival was followed at a minimum of 7 years or until death. S-IGF-II levels were higher in IS cases both in the acute phase and at 3-month follow-up compared to controls (p < 0.05 and p < 0.01, respectively). The lowest quintile of acute s-IGF-II was, compared to the four higher quintiles, associated with an increased risk of post-stroke mortality (median follow-up 10.6 years, crude hazard ratio (HR) 2.34, 95% confidence interval (CI) 1.56–3.49, and fully adjusted HR 1.64, 95% CI 1.02–2.61). In contrast, crude associations with poor functional outcome (mRS 3–6) lost significance after full adjustment for covariates. In conclusion, s-IGF-II was higher in IS cases than in controls, and low acute s-IGF-II was an independent risk marker of increased mortality.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

Effects of Maternal Diabetes on Fetal Expression of Insulin-Like Growth Factor and Insulin-Like Growth Factor Binding Protein MRNAs in the Rat

1995 ◽  
Vol 147 (2) ◽  
pp. R5-R8 ◽  
Author(s):  
Randal D. Streck ◽  
Veeraramani S. Rajaratnam ◽  
Renata B. Fishman ◽  
Peggy J. Webb
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Expression Patterns ◽  
Maternal Diabetes ◽  
Limb Bud ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Increased Risk

ABSTRACT Matemal diabetes is associated in humans and rats with an increased risk for fetal growth abnormalities and malformations. Therefore, the effect of maternal diabetes on expression of genes that regulate fetal growth and differentiation is of considerable interest. Developmental growth is regulated in part by the expression and availability of insulin-like growth factors (IGFs). Postnatal expression of a subset of the IGFs and IGF binding proteins (IGFBPs) has been demonstrated to be regulated in response to diabetes and other metabolic conditions. We used in situ hybridization to analyze the effect of maternal diabetes, induced by streptozotocin (STZ) prior to mating, upon prenatal rat IGF and IGFBP mRNA expression. At gestational day (GD) 14, the most striking effect of maternal diabetes on fetal IGF/IGFBP gene expression was a marked increase in the abundance of IGFBP-1 mRNA within the liver primordia of fetuses isolated from diabetic dams compared to age-matched controls. This upregulation cannot be entirely due to the approximately one-half-day delay in fetal development (based on limb bud staging) associated with maternal diabetes, as there was no gross difference in the level of IGFBP-1 mRNA between GD13 and GD14 control fetal livers. In contrast, the fetal mRNA expression patterns of IGF-I, IGF-II and IGFBP-2, -3, -4, -5 and -6 were not grossly altered by maternal diabetes. These data are consistent with the hypothesis that IGFBP-1 produced within the fetal liver and secreted into fetal circulation may play a role in regulating rat fetal growth.

Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters

1996 ◽  
Vol 149 (1) ◽  
pp. 117-124 ◽  
Author(s):  
X Li ◽  
H Cui ◽  
B Sandstedt ◽  
H Nordlinder ◽  
E Larsson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Human Liver ◽  
Fetal Liver ◽  
Adult Life ◽  
Absolute Amount ◽  
Insulin Like Growth Factor ◽  
Rnase Protection ◽  
Highly Active ◽  
Age Related ◽  
Factor Ii

Abstract We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The PI promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts. Journal of Endocrinology (1996) 149, 117–124

Abstract T P130: High Serum Insulin-Like Growth Factor 1 is Associated with Lower Risk of Ischemic Stroke: The Framingham Heart Study

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Hamidreza Saber ◽  
Jayandra J Himali ◽  
Alexa Beiser ◽  
Ashkan Shoamanesh ◽  
Alexandra Pikula ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Lower Risk ◽  
Serum Insulin ◽  
High Serum ◽  
Community Dwelling ◽  
Insulin Like Growth Factor ◽  
Original Cohort ◽  
Cross Sectional ◽  
Cox Models

Background: Insulin-like growth factor 1 (IGF-1), reduces progression of atherosclerosis and in cross-sectional studies low circulating IGF-1 is associated with increased carotid intima-media thickness. Yet, prospective data linking IGF-1 levels to development of stroke remain sparse and inconsistent. We related circulating IGF-1 levels to risk of incident stroke in a community-dwelling sample. Methods: Serum IGF-1 levels were assayed in 757 stroke-free participants (age 79+5 years, 62% women) from the Framingham original cohort (1990-1994), and related to prospectively ascertained, incident all-stroke and ischemic stroke using Cox models. Results: During a mean follow-up of 10.2 years in 757 participants, 119 developed stroke including 99 with ischemic stroke. After adjustment for age and sex, higher log-IGF1 levels were associated with a lower risk of incident ischemic stroke [hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.63- 0.99, p=0.043]. There was a threshold effect with subjects in the lowest quintile of IGF-1 levels having 2.56-fold higher risk of incident ischemic stroke (95% CI: 1.20, 5.45, p=0.015) compared to all others. We observed significant interaction between diabetes and IGF1 in their relation to ischemic stroke (p=0.016). In pre-specified subgroup analyses the effect was restricted to persons with diabetes and central obesity (waist-to-hip ratio in top quartile) in whom each SD increase in IGF-1 was associated with a 61% (HR: 0.39, 95%CI: 0.20-0.78, p=0.007), and 41% (HR: 0.59, 95%CI: 0.37- 0.95, p=0.031) lower risk of incident ischemic stroke, respectively. Results were similar for all-stroke. Conclusions: IGF-1 may have a protective role in the pathogenesis of ischemic stroke among persons with insulin resistance as manifested by diabetes and/or obesity.

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